Most of our understanding regarding the cellular reservoirs that maintain viral persistence has been derived from studies with lymphocytes. In contrast, the role played by myeloid-lineage cells (e.g., monocyte/macrophage and dendritic cells) in viral replication and persistence is not well understood. Our ongoing studies indicate that primate lentiviruses have evolved functions that specifically allow them to establish persistent reservoirs within myeloid-lineage cells. As the field now explores strategies that attempt to eradicate the virus from infected individuals, an understanding of the role played by myeloid-lineage cells in viral replication and persistence is essential. In this Project, we propose experiments that will define the role for macrophages in viral persistence and that will explore a strategy for removal of this potential viral reservoir in vivo. Our broadly-defined objectives are to define the mechanisms whereby HIV persists in macrophages (focusing on an HIV-induced survival pathway mediated by monocyte colony stimulating factor, or MCSF) and to define with precision the geospatial distribution of latently-infected cells in optimally treated hosts. In Aim 1, we will determine the molecular mechanisms of macrophage latency as well as a strategy to interrupt this mechanism. We will also characterize the impact of MCSF and MCSF antagonists on chronic/latent infection of macrophage in vitro. This information will guide a strategy to purge infected macrophage in vivo (Aim 3 and Project 1). In Aim 2, we will determine whether macrophages maintain viral persistence in the face of antiretroviral suppression. More specifically, we will characterize the viral genomes in tissue macrophages isolated from lymph node and gut-associated lymphoid tissue of patients on suppressive ART (with Project 6) and we will exploit the non-human primate model to extend our sampling of tissue macrophages into compartments not readily accessible in HIV-infected patients (with Project 1). Finally, in Aim 3, we will test strategies to purge infected macrophage in non-human primates. In direct association with analogous studies carried out in Project 1, we will examine whether MCSF antagonism eradicates SIV from the macrophage reservoir of the non-human primate.